1. Field of the Invention
The present invention relates to novel carbapenem derivatives which have excellent antibiotic activity against a wide spectrum of bacteria, and more particularly to novel carbapenem derivatives which have a substituted imidazo[5,1-b]thiazole group at the 2-position on the carbapenem ring.
2. Related Art
Carbapenem derivatives, by virtue of potent antibiotic activity against a wide-spectrum of bacteria, have been energetically studied as a highly useful xcex2-lactam agent, and Imipenem, Panipenem, and Meropenem have already been clinically used.
At the present time, both Imipenem and Panipenem, however, are used as a mixture due to instability against renal dehydropeptidase-1 (hereinafter abbreviated to xe2x80x9cDHP-1xe2x80x9d) in the case of Imipenem and in order to reduce nephrotoxicity in the case of Panipenem. Meropenem which has recently been marketed has a methyl group at the 1xcex2-position, so that it has increased stability against DHP-1 and thus can be used alone. The stability against DHP-1, however, is still unsatisfactory. The antibiotic activity also is not necessarily satisfactory against methicillin resistant Staphylococcus aureus (hereinafter abbreviated to xe2x80x9cMRSAxe2x80x9d), penicillin resistant Streptococcus pneumoneae (hereinafter abbreviated to xe2x80x9cPRSPxe2x80x9d), resistant Pseudomonas aeruginosa, enterococci, and Influenzavirus which currently pose serious clinical problems. Therefore, drugs useful for these bacteria responsible for infectious diseases have been desired in the art.
WO 96/28455 describes carbapenem derivatives having a novel aromatic heterocyclic imidazo[5,1-b]thiazolium-6-ylmethyl group at the 2-position of the carbapenem ring, WO 98/23623 describes carbapenem derivatives having an imidazo[5,1-b]thiazole group through a pyrrolidinylthio group at the 2-position of the carbapenem ring, and WO 98/32760 describes derivatives with a carbon atom on an imidazo[5,1-b]thiazole group being attached to the 2-position of the carbapenem ring.
An object of the present invention is to provide carbapenem derivatives which have potent antibiotic activity against MRSA, PRSP, Influenzavirus, and xcex2-lactamase-producing bacteria and are stable against DHP-1.
According to one aspect of the present invention, there is provided a compound represented by formula (I) or a pharmaceutically acceptable salt thereof: 
wherein
R1 represents a hydrogen atom or methyl;
R2 and R3, which may be the same or different, each independently represent
a hydrogen atom,
a halogen atom,
lower alkyl on which one or more hydrogen atoms are optionally substituted by hydroxyl or amino,
lower alkylcarbonyl,
carbamoyl,
aryl, or
lower alkylthio;
R4 represents
lower alkylthio on which one or more hydrogen atoms are optionally substituted by a group selected from the group consisting of: a halogen atom; nitro; azido; cyano; lower cycloalkyl; lower alkylthio; hydroxyl; lower alkoxy; phosphonoxy; formyl; lower alkylcarbonyl; arylcarbonyl; carboxy; lower alkoxycarbonyl; carbamoyl; N-lower alkylcarbamoyl; N,N-di-lower alkylcarbamoyl; amino; N-lower alkylamino; N,N-di-lower alkylamino; formylamino; lower alkylcarbonylamino; aminosulfonylamino; (N-lower alkylamino)sulfonylamino; (N,N-di-lower alkylamino)-sulfonylamino; formimidoylamino; acetimidoylamino; guanidino; aminosulfonyl; (N-lower alkylamino)sulfonyl; (N,N-di-lower alkylamino)sulfonyl; aryl; a monocyclic or bicyclic heterocyclic ring containing one or more hetero atoms which may be the same or different; pyridinium-1-yl; 1-azonia-4-azabicyclo[2,2,2]oct-1-yl; and 4-lower alkyl-1,4-diazoniabicyclo[2,2,2]oct-1-yl wherein one or more hydrogen atoms of the lower alkyl portion are optionally substituted by a group selected from the group consisting of a halogen atom, hydroxyl, carbamoyl, and amino,
lower cycloalkylthio wherein one or more hydrogen atoms of the cycloalkyl portion are optionally substituted by a group selected from the group consisting of a halogen atom, nitro, cyano, hydroxyl, carbamoyl, and amino,
C2-4 alkenylthio,
C2-4 alkynylthio,
arylthio,
thio substituted by a monocyclic or bicyclic heterocyclic ring containing one or more hetero atoms which may be the same or different,
lower alkylsulfinyl wherein one or more hydrogen atoms of the alkyl portion are optionally substituted by a group selected from the group consisting of halogen atom, hydroxyl, carbamoyl, and amino,
lower alkylsulfonyl wherein one or more hydrogen atoms of the alkyl portion are optionally substituted by a group selected from the group consisting of a halogen atom, hydroxyl, carbamoyl, and amino,
lower alkylcarbonyl, or
arylcarbonyl or
R4 and R5 together form xe2x80x94R4xe2x80x94R5xe2x80x94 which represents xe2x80x94Sxe2x80x94(CH2)nxe2x80x94 wherein n is an integer of 2 to 4;
R5 represents
lower alkyl on which one or more hydrogen atoms are optionally substituted by a group selected from the group consisting of: a halogen atom; nitro; azido; cyano; lower cycloalkyl; lower alkylthio wherein one or more hydrogen atoms of the alkyl portion are optionally substituted by a halogen atom, hydroxyl, carbamoyl, or amino; thio substituted by a monocyclic or bicyclic heterocyclic ring containing one or more hetero atoms which may be the same or different, wherein one or more hydrogen atoms of the ring are optionally substituted by carbamoyl, hydroxymethyl, aminosulfonylamino, or aminosulfonylaminomethyl; isothioureido; hydroxyl; lower alkoxy on which one or more hydrogen atoms are optionally substituted by a halogen atom, hydroxyl, carbamoyl, or amino; phosphonoxy; formyl; lower alkylcarbonyl; arylcarbonyl wherein one or more hydrogen atoms of the aryl portion are optionally substituted by a group selected from the group consisting of a halogen atom, nitro, cyano, lower alkyl on which one or more hydrogen atoms are optionally substituted by a halogen atom, hydroxyl, carbamoyl, or amino, hydroxyl, lower alkoxy, benzyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, amino, and hydroxyamino; carboxy; lower alkoxycarbonyl; carbamoyl; N-aminocarbamoyl; N-lower alkylcarbamoyl wherein one or more hydrogen atoms of the alkyl portion are optionally substituted by amino, formimidoylamino, acetimidoylamino, or hydroxyl; N,N-di-lower alkylcarbamoyl wherein one or more hydrogen atoms of the alkyl portion are optionally substituted by amino, formimidoylamino, acetimidoylamino, or hydroxyl; alicyclic aminocarbonyl in which one or more hetero atoms may be contained as the member atom of the ring; N-arylcarbamoyl; N-hydroxycarbamoyl; N-benzyloxy-carbamoyl; N-lower alkyl-N-lower alkoxycarbamoyl; hydrazinocarbonyl; amino; N-lower alkylamino wherein one or more hydrogen atoms of the alkyl portion are optionally substituted by amino, formimidoylamino, acetimidoylamino, or hydroxyl; N,N-di-lower alkylamino wherein one or more hydrogen atoms of the alkyl portion are optionally substituted by amino, formimidoylamino, acetimidoylamino, or hydroxyl; formylamino; lower alkylcarbonylamino; aminosulfonylamino; (N-lower alkylamino)sulfonylamino; (N,N-di-lower alkylamino)sulfonylamino; piperazinyl-carbonylamino; N-lower alkylpiperazinylcarbonylamino; N-arylpiperazinylcarbonylamino; formimidoylamino; acetimidoylamino; guanidino; lower alkylsulfonyl wherein one or more hydrogen atoms of the alkyl portion are optionally substituted by a halogen atom, amino, or hydroxyl; arylsulfonyl wherein one or more hydrogen atoms of the aryl portion are optionally substituted by a halogen atom, amino, or hydroxyl; aminosulfonyl; (N-lower alkylamino)sulfonyl; (N,N-di-lower alkylamino)sulfonyl; aryl on which one or more hydrogen atoms are optionally substituted by a group selected from the group consisting of a halogen atom, nitro, cyano, lower alkyl on which one or more hydrogen atoms are optionally substituted by a halogen atom, hydroxyl, carbamoyl, N,N-di-lower alkylcarbamoyl, amino, or amino-substituted lower alkyl, hydroxyl, lower alkoxy, benzyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl N,N-di-lower alkylcarbamoyl, amino, and hydroxyamino; and a monocyclic or bicyclic aliphatic or heteroaromatic ring, containing one or more hetero atoms which may be the same or different, wherein one or more hydrogen atoms of the ring are optionally substituted by a halogen atom, hydroxyl, carbamoyl, or amino and, when the ring contains a nitrogen atom, lower alkyl optionally substituted by carbamoyl may be attached to the nitrogen atom and, in addition, the nitrogen atom may be in the form of a quaternary ammonium atom,
lower cycloalkyl,
C2-4 alkenyl,
C2-4 alkynyl,
a four- to seven-membered aliphatic heterocyclic ring containing one or more nitrogen atoms, wherein the heterocyclic ring may further comprise one or more oxygen or sulfur atoms as the ring member atom and one or more hydrogen atoms on the carbon atoms in the heterocyclic ring are optionally substituted by a group selected from the group consisting of: lower alkyl on which one or more hydrogen atoms are optionally substituted by hydroxyl or amino; carboxy; lower alkoxycarbonyl; carbamoyl; N-lower alkylcarbamoyl; and N,N-di-lower alkylcarbamoyl, and wherein a hydrogen atom on the nitrogen atom in the heterocyclic ring is optionally substituted by lower alkyl, C2-4 alkenyl, formimidoyl, acetimidoyl, or amidino, or
a group selected from the following groups: 
According to another aspect of the present invention, there is provided a pharmaceutical composition comprising as active ingredient a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. This pharmaceutical composition is useful for the treatment and/or prevention of infectious diseases.
According to still another aspect of the present invention, there is provided use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, for the manufacture of the medicament.
According to a further aspect of the present invention, there is provided a method for treating and/or preventing infectious diseases, comprising the step of administering a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in an amount effective for the treatment and/or prevention of infectious diseases, to mammals including humans.
The carbapenem derivatives represented by formula (I) have potent antibiotic activities against a wide spectrum of Gram-positive bacteria and Gram-negative bacteria. The compounds represented by formula (I) have potent antibiotic activity particularly against MRSA, PRSP, Influenzavirus, and xcex2-lactamase-producing bacteria. The carbapenem derivatives of the present invention advantageously have low toxicity and high safety.